Neoangiogenesis and p53 protein in lung cancer: their prognostic role and their relation with vascular endothelial growth factor (VEGF) expression.

Following up-regulation of an angiogenesis inhibitor by the wild-type p53 protein proven recently, we have analysed on the one hand the prognostic impact of microvessel count (MC) and p53 protein overexpression in non-small-cell lung carcinoma (NSCLC) progression and, on the other hand, the inter-relation between the microvascular pattern and the p53 protein expression. Moreover, we assessed the expression of vascular endothelial growth factor (VEGF), one of the pivotal mediators of tumour angiogenesis, in order to investigate its relation to p53 protein expression and MC. Tumours from 73 patients resected for NSCLC between March 1991 and April 1992 (median follow-up 47 months, range 32-51 months) were analysed using an immunohistochemical method. In univariate analysis, MC and p53 accumulation were shown to affect metastatic nodal involvement, recurrence and death significantly. Multiple logistic regression analysis showed an important prognostic influence of MC and nodal status on overall (P = 0.0009; P = 0.01) and disease-free survival (P = 0.0001; P = 0.03). Interestingly, a strong statistical association was observed between p53 nuclear accumulation and MC (P = 0.0003). The same inter-relationship was found in non-squamous histotype (P = 0.002). When we analysed the concomitant influence of MC and p53 expression on overall survival, we were able to confirm a real predominant role of MC in comparison with p53. With regard to VEGF expression, p53-negative and lowly vascularized tumours showed a mean VEGF expression significantly lower than p53-positive and highly vascularized cancers (P = 0.02). These results underline the prognostic impact of MC and p53 protein accumulation in NSCLC and their reciprocal inter-relationship, supporting the hypothesis of a wild-type p53 regulation on the angiogenetic process through a VEGF up-regulation

Prognostic significance of osteopontin expression in early-stage non-small-cell lung cancer

Osteopontin (OPN) is a multifunctional protein, which has recently been shown to be linked to tumorigenesis, progression and metastasis in different malignancies. Since non-small-cell lung cancer (NSCLC)'s prognosis remains bad, with few predictors of outcome, the purpose of this study was to evaluate if OPN might be involved in NSCLC's biology and therefore represent a prognostic marker and a target for new therapeutic trials. Immunohistochemistry was used to detect OPN expression, evaluated as percentage of neoplastic cells with cytoplasmic immunoreactivity, in a wide cohort of patients with stage I NSCLC (136 cases). The median value of this series (20% of positive cells) was used as the cutoff value to distinguish tumours with low (<20%) from tumours with high (⩾20%) OPN expression. A statistically significant correlation between high levels of OPN and shorter overall (P=0.034) and disease-free (P=0.011) survival in our patients was shown. Our results support the hypothesis that high OPN expression is a significantly unfavourable prognostic factor for the survival of patients with stage I NSCLC. This conclusion has notable importance in terms of the biological characterization of early-stage tumours and therapeutic opportunities

Spatial Dynamics Of Vertical And Horizontal Intergovernmental Collaboration

Although researchers have made progress in understanding motivations behind local government collaboration, there is little research that explores the spatial dynamics of such interactions. Does the idea of collaboration travel horizontally, passed from neighbor to neighbor, or is vertical leadership from state, county, or regional actors more important in influencing local governments’ decisions to share resources and functions? What factors influence local governments’ choices to collaborate with their neighbors versus a regional entity, county, or state government? In this article, we investigate the importance of vertical and horizontal influences when local governments decide to collaborate around land use planning. Using data from a survey of Michigan local government officials, we take a spatial statistical approach to answering this question. We find widespread evidence of collaboration at multiple scales, and observe patterns of both horizontal and vertical influence. We also find that contextual factors help to explain these patterns of collaboration.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/112248/1/juaf12139.pd

Conventional and molecular cytogenetics of human non-medullary thyroid carcinoma: characterization of eight cell line models and review of the literature on clinical samples

<p>Abstract</p> <p>Background</p> <p>Cell lines are often poorly characterized from a genetic point of view, reducing their usefulness as tumor models. Our purpose was to assess the genetic background of eight commonly used human thyroid carcinoma models and to compare the findings with those reported for primary tumors of the gland.</p> <p>Methods</p> <p>We used chromosome banding analysis and comparative genomic hybridization to profile eight non-medullary thyroid carcinoma cell lines of papillary (TPC-1, FB2, K1 and B-CPAP), follicular (XTC-1) or anaplastic origin (8505C, C643 and HTH74). To assess the representativeness of the findings, we additionally performed a thorough review of cytogenetic (n = 125) and DNA copy number information (n = 270) available in the literature on clinical samples of thyroid carcinoma.</p> <p>Results</p> <p>The detailed characterization of chromosomal markers specific for each cell line revealed two cases of mistaken identities: FB2 was shown to derive from TPC-1 cells, whereas K1 cells have their origin in cell line GLAG-66. All cellular models displayed genomic aberrations of varying complexity, and recurrent gains at 5p, 5q, 8q, and 20q (6/7 cell lines) and losses at 8p, 13q, 18q, and Xp (4/7 cell lines) were seen. Importantly, the genomic profiles were compatible with those of the respective primary tumors, as seen in the meta-analysis of the existing literature data.</p> <p>Conclusion</p> <p>We provide the genomic background of seven independent thyroid carcinoma models representative of the clinical tumors of the corresponding histotypes, and highlight regions of recurrent aberrations that may guide future studies aimed at identifying target genes. Our findings further support the importance of routinely performing cytogenetic studies on cell lines, to detect cross-contamination mishaps such as those identified here.</p

Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma:a paradigm shift to reduce overtreatment of indolent tumors

Although growing evidence points to highly indolent behavior of encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC), most patients with EFVPTC are treated as having conventional thyroid cancer

Central carbon metabolism in the progression of mammary carcinoma

There is a growing belief that the metabolic program of breast tumor cells could be a therapeutic target. Yet, without detailed information on central carbon metabolism in breast tumors it is impossible to know which metabolic pathways to target, and how their inhibition might influence different stages of breast tumor progression. Here we perform the first comprehensive profiling of central metabolism in the MCF10 model of mammary carcinoma, where the steps of breast tumor progression (transformation, tumorigenicity and metastasis) can all be examined in the context of the same genetic background. The metabolism of [U-13C]-glucose by a series of progressively more aggressive MCF10 cell lines was tracked by 2D NMR and mass spectrometry. From this analysis the flux of carbon through distinct metabolic reactions was quantified by isotopomer modeling. The results indicate widespread changes to central metabolism upon cellular transformation including increased carbon flux through the pentose phosphate pathway (PPP), the TCA cycle, as well as increased synthesis of glutamate, glutathione and fatty acids (including elongation and desaturation). The de novo synthesis of glycine increased upon transformation as well as at each subsequent step of breast tumor cell progression. Interestingly, the major metabolic shift in metastatic cells is a large increase in the de novo synthesis of proline. This work provides the first comprehensive view of changes to central metabolism as a result of breast tumor progression

KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer

BACKGROUND: KRAS codons 12 and 13 mutations predict resistance to anti-EGFR monoclonal antibodies (moAbs) in metastatic colorectal cancer. Also, BRAF V600E mutation has been associated with resistance. Additional KRAS mutations are described in CRC. METHODS: We investigated the role of KRAS codons 61 and 146 and BRAF V600E mutations in predicting resistance to cetuximab plus irinotecan in a cohort of KRAS codons 12 and 13 wild-type patients. RESULTS: Among 87 KRAS codons 12 and 13 wild-type patients, KRAS codons 61 and 146 were mutated in 7 and 1 case, respectively. None of mutated patients responded vs 22 of 68 wild type (P = 0.096). Eleven patients were not evaluable. KRAS mutations were associated with shorter progression-free survival (PFS, HR: 0.46, P = 0.028). None of 13 BRAF-mutated patients responded vs 24 of 74 BRAF wild type (P = 0.016). BRAF mutation was associated with a trend towards shorter PFS (HR: 0.59, P = 0.073). In the subgroup of BRAF wild-type patients, KRAS codons 61/146 mutations determined a lower response rate (0 vs 37%, P = 0.047) and worse PFS (HR: 0.45, P = 0.023). Patients bearing KRAS or BRAF mutations had poorer response rate (0 vs 37%, P = 0.0005) and PFS (HR: 0.51, P = 0.006) compared with KRAS and BRAF wild-type patients. CONCLUSION: Assessing KRAS codons 61/146 and BRAF V600E mutations might help optimising the selection of the candidate patients to receive anti-EGFR moAbs. British Journal of Cancer (2009) 101, 715-721. doi: 10.1038/sj.bjc.6605177 www.bjcancer.com Published online 14 July 2009 (C) 2009 Cancer Research U

Tales of future weather

Society is vulnerable to extreme weather events and, by extension, to human impacts on future events. As climate changes weather patterns will change. The search is on for more effective methodologies to aid decision-makers both in mitigation to avoid climate change and in adaptation to changes. The traditional approach uses ensembles of climate model simulations, statistical bias correction, downscaling to the spatial and temporal scales relevant to decision-makers, and then translation into quantities of interest. The veracity of this approach cannot be tested, and it faces in-principle challenges. Alternatively, numerical weather prediction models in a hypothetical climate setting can provide tailored narratives for high-resolution simulations of high-impact weather in a future climate. This 'tales of future weather' approach will aid in the interpretation of lower-resolution simulations. Arguably, it potentially provides complementary, more realistic and more physically consistent pictures of what future weather might look like

Interaction between gemcitabine and topotecan in human non-small-cell lung cancer cells: effects on cell survival, cell cycle and pharmacogenetic profile

The pyrimidine analogue gemcitabine is an established effective agent in the treatment of non-small-cell lung cancer (NSCLC). The present study investigates whether gemcitabine would be synergistic with the topoisomerase I inhibitor topotecan against the NSCLC A549 and Calu-6 cells. Cells were treated with gemcitabine and topotecan for 1 h and the type of drug interaction was assessed using the combination index (CI). Cell cycle alterations were analysed by flow cytometry, while apoptosis was examined by the occurrence of DNA internucleosomal fragmentation, nuclear condensation and caspase-3 activation. Moreover, the possible involvement of the PI3K-Akt signalling pathway was investigated by the measurement of Akt phosphorylation. Finally, quantitative, real-time PCR (QRT-PCR) was used to study modulation of the gemcitabine-activating enzyme deoxycytidine kinase (dCK) and the cellular target enzyme ribonucleotide reductase (RR). In results, it was found that simultaneous and sequential topotecan → gemcitabine treatments were synergistic, while the reverse sequence was antagonistic in both cell lines. DNA fragmentation, nuclear condensation and enhanced caspase-3 activity demonstrated that the drug combination markedly increased apoptosis in comparison with either single agent, while cell cycle analysis showed that topotecan increased cells in S phase. Furthermore, topotecan treatment significantly decreased the amount of the activated form of Akt, and enhanced the expression of dCK (+155.0 and +115.3% in A549 and Calu-6 cells, respectively), potentially facilitating gemcitabine activity. In conclusion, these results indicate that the combination of gemcitabine and topotecan displays schedule-dependent activity in vitro against NSCLC cells. The gemcitabine → topotecan sequence is antagonistic while drug synergism is obtained with the simultaneous and the sequential topotecan → gemcitabine combinations, which are associated with induction of decreased Akt phosphorylation and increased dCK expression

Variability of Female Responses to Conspecific vs. Heterospecific Male Mating Calls in Polygynous Deer: An Open Door to Hybridization?

Males of all polygynous deer species (Cervinae) give conspicuous calls during the reproductive season. The extreme interspecific diversity that characterizes these vocalizations suggests that they play a strong role in species discrimination. However, interbreeding between several species of Cervinae indicates permeable interspecific reproductive barriers. This study examines the contribution of vocal behavior to female species discrimination and mating preferences in two closely related polygynous deer species known to hybridize in the wild after introductions. Specifically, we investigate the reaction of estrous female red deer (Cervus elaphus) to playbacks of red deer vs. sika deer (Cervus nippon) male mating calls, with the prediction that females will prefer conspecific calls. While on average female red deer preferred male red deer roars, two out of twenty females spent more time in close proximity to the speaker broadcasting male sika deer moans. We suggest that this absence of strict vocal preference for species-specific mating calls may contribute to the permeability of pre-zygotic reproductive barriers observed between these species. Our results also highlight the importance of examining inter-individual variation when studying the role of female preferences in species discrimination and intraspecific mate selection